K433 Acetylation Switches PKM2 to a Nuclear Kinase

The pyruvate kinase isoform M2 (PKM2) is normally expressed in embryonic tissues but is specifically reexpressed in many cancers and thought to play a central role in tumor metabolism. However, PKM2 has also been found to phosphorylate proteins and regulate transcription in the nucleus, raising the possibility that PKM2 plays nonmetabolic roles in cancer. Lv and colleagues sought to determine how PKM2 activity is regulated and whether a functional switch of PKM2 to a nuclear protein kinase plays a role in cell growth and transformation. Hypothesizing that a posttranslational modification might control PKM2 function, the authors focused on lysine 433 (K433), a highly conserved, PKM2-specific residue previously found to be acetylated in proteomic analyses. K433 was a major PKM2 acetylation site in human cells and was directly acetylated by the p300 acetyltransferase. K433 acetylation disrupted binding of the PKM2 allosteric activator fructose 1,6-bisphosphate (FBP), which in turn prevented tetramerization and activation of PKM2. Importantly, in addition to reducing cytoplasmic pyruvate kinase activity, K433 acetylation led to an accumulation of dimeric and monomeric PKM2 in the nucleus and a marked increase in nuclear protein kinase activity. Acetylation of K433 was reduced in quiescent or contact-inhibited cells and increased upon exposure to growth factors or human papillomavirus oncoproteins, indicating that mitogenic and oncogenic signals induce K433 acetylation. Cancer cell lines expressing only an acetyl-mimetic K433Q PKM2 mutant grew more rapidly in culture and in nude mice than cells expressing wild-type PKM2 or a nonacetylatable K433R mutant, and K433 acetylation was significantly elevated in human breast cancer samples compared with adjacent normal tissue, further supporting a role for PKM2 K433 acetylation in tumorigenesis. Together, these findings suggest that the oncogenic activity of PKM2 may be nuclear and dependent on a K433 acetylation-mediated functional switch.

Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell 2013;52:340–52.

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